Diving into Batch-to-Batch Variability of Topical Products-a Regulatory Bottleneck

Abstract

Purpose

Following the recent European Medicine Agency (EMA) draft guideline on quality and equivalence of topical products, a modular framework for bioequivalence assessment is proposed, wherein the qualitative, quantitative, microstructure and product performance sameness is demanded to support generic applications. Strict regulatory limits are now imposed, but, the suitability of these limits has been subject of intense debate. In this context, this paper aims to address these issues by characterizing a panel of 8 reference blockbuster semisolid topical products.

Methods

For each product, three batches were selected and, whenever possible, batches retrieved from different manufacturing sites were considered. Product microstructure was evaluated in terms of globule size, pH, rheological attributes and, if required, the thermal behaviour was also assessed. Performance was evaluated through in vitro release testing (IVRT). Finally, an integrated multivariate analysis was performed to highlight the features that most contribute for product variability.

Results

Marked differences were registered within reference products. Statistical analysis demonstrated that if EMA criteria are applied, none of the same product batches can be considered as equivalent. Rheological parameters as well as IVRT indicators account for the majority of batch-to-batch differences.

Conclusions

Semisolid dosage forms exhibit intrinsic variability. This calls for the attention to the need of establishing reasonable equivalence criteria applied to generic drug products.

Graphical abstract

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Abbreviations

ACV:

Acyclovir

API:

Active pharmaceutical ingredient

BCS:

Biopharmaceutical classification system

BFZ:

Bifonazole

C:

Compliant

CES:

Clinical endpoint studies

CI:

Confidence intervals

CLB:

Clobetasol

CLT:

Clotrimazole

CQA:

Critical quality attributes

CV:

Coefficient of variation

DF:

Diclofenac

EMA:

European Medicine Agency

ETF:

Etofenamate

G´:

Storage modulus

G´´:

Loss Modulus

HC:

Hydrocortisone

HCA:

Hierarchical cluster analysis

HPLC:

High performance liquid chromatography

IVPT:

In vitro permeation testing

IVRR:

In vitro release rate

IVRT:

In vitro release testing

LVR:

Linear viscoelastic region

MW:

Molecular weight

NC:

Non-compliant

NSAIDs:

Non-steroid anti-inflammatory drugs

PBS:

Phosphate buffered ased saline

PCA:

Principal component analysis

Q final point:

Cumulative amount of drug released at the end of IVRT

Q initial point:

Cumulative amount of drug released in the beginning of IVRT

SS:

Statistical significance

TCZ:

Tioconazole

TGP:

Topical generic product

US-FDA:

US Food and Drug Administration

USP:

United States Pharmacopeia

VDC:

Vertical diffusion cell

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Acknowledgments

Margarida Miranda acknowledges the PhD grant PD/BDE/135075/2017 assigned by FCT (Fundação para a Ciência e Tecnologia, Portugal) and Laboratórios Basi from Drugs R&D Doctoral Program. Tânia Cova also acknowledges the Junior Research grant CEECIND/00915/2018 assigned by FCT. The authors also acknowledge the Coimbra Chemistry Centre, supported by FCT, through the Project UID/QUI/00313/2020.

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Miranda, M., Cova, T., Augusto, C. et al. Diving into Batch-to-Batch Variability of Topical Products-a Regulatory Bottleneck. Pharm Res 37, 218 (2020). https://doi.org/10.1007/s11095-020-02911-y

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Keywords

  • batch variability
  • EMA
  • IVRT
  • Rheology
  • topical products